feature articles
Reviews and
Molecular mechanisms in allergy and clinical immunology
Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, William T. Shearer, MD, PhD, and Donata
Vercelli, MD
Mechanisms of allergen-specific
immunotherapy
Mübeccel Akdis, MD, PhD, and Cezmi A. Akdis, MD Davos, Switzerland
This activity is available for CME credit. See page 48A for important information.
Allergen-specific immunotherapy (SIT) has been used for
almost a century as a desensitizing therapy for allergic diseases
and represents the only curative and specific method of
treatment. Administration of appropriate concentrations of
allergen extracts has been shown to be reproducibly effective
when patients are carefully selected. The mechanisms by which
allergen-SIT has its effects include the modulation of T-cell and
B-cell responses and related antibody isotypes as well as
effector cells of allergic inflammation, such as eosinophils,
basophils, and mast cells. The balance between allergen-specific
T-regulatory (Treg) and TH2 cells appears to be decisive in the
development of allergic and healthy immune responses against
allergens. Treg cells consistently represent the dominant subset
specific for common environmental allergens in sensitized
healthy individuals. In contrast, there is a high frequency of
allergen-specific TH2 cells in patients with allergy. The
induction of a tolerant state in peripheral T cells represents an
essential step in allergen-SIT. Peripheral T-cell tolerance is
characterized mainly by generation of allergen-specific Treg
cells leading to suppressed T-cell proliferation and TH1 and
TH2 cytokine responses against the allergen. This is
accompanied by a significant increase in allergen-specific IgG4,
and also IgG1 and IgA, and a decrease in IgE in the late stage of
the disease. In addition, decreased tissue infiltration of mast
cells and eosinophils and their mediator release including
From the Swiss Institute of Allergy and Asthma Research.
The authors’ laboratories are supported by Swiss National Science Foundation
grants 32-112306 and 32-105268 and the Global Allergy and Asthma
European Network.
Disclosure of potential conflict of interest: M. Akdis has received grant support
from ALK-Abelló, Stallergenes, Allergopharma Joachim Ganzer KG, Essex
Chemie, Allecure, the Global Allergy Asthma European Network, and the
Swiss National Science Foundation and is on the speakers’ bureau for
ALK-Abelló. C. A. Akdis has received grant support from ALK-Abelló,
Stallergenes, Allergopharma Joachim Ganzer KG, Essex Chemie,
Allecure, the Global Allergy Asthma European Network, and the Swiss
National Science Foundation and is on the speakers’ bureau for Stallergenes,
Allergopharma Joachim Ganzer KG, and Merck.
Received for publication December 11, 2006; revised January 14, 2007;
accepted for publication January 16, 2007.
Available online March 6, 2007.
Reprint requests: Cezmi A. Akdis, MD, Swiss Institute of Allergy and Asthma
Research, Obere Strasse 22, CH7270 Davos, Switzerland. E-mail: akdisac@
siaf.unizh.ch.
0091-6749/$32.00
Ó 2007 American Academy of Allergy, Asthma & Immunology
doi:10.1016/j.jaci.2007.01.022
780
circulating basophils takes place. Current understanding of
mechanisms of allergen-SIT, particularly the role of Treg cells
in peripheral tolerance, may enable novel treatment strategies.
(J Allergy Clin Immunol 2007;119:780-9.)
Key words: Allergen immunotherapy, T-regulatory cells, tolerance,
IgE, IgG, T cells, B cells, mast cells, basophils, eosinophils, IL-10,
TGF-b
The physiopathology of allergic immune responses is
complex and has been shown to be influenced by several
factors, including genetic susceptibility, route of expo-
sure, allergen dose, and, in some cases, the structural
characteristics of the allergen.1 Allergic immune response
requires sensitization and development of specific im-
mune response toward the allergen. During sensitization
to allergen, priming of allergen-specific CD41 TH2 cells
results in the production of TH2 cytokines (such as IL-4
and IL-13) that are responsible for class switching to
the e heavy chain for IgE production by B cells, mucus
production, and activation of endothelial cells for TH2
cell and eosinophil migration to tissues.2,3 IgE sensitizes
mast cells and basophils by binding to the high-affinity
receptor for IgE (FceRI) expressed on their surface. On
cross-linking of the IgE-FceRI complexes by allergen,
mast cells and basophils degranulate, releasing vasoactive
amines (principally histamine), lipid mediators (prosta-
glandins and cysteinyl leukotrienes), cytokines, and che-
mokines, all of which characterize the immediate phase
of the allergic reaction.2,3 After the sensitization phase,
allergic inflammation and reactions to allergen challenge
are observed in the target organ, leading to development
of allergic rhinoconjunctivitis, eczema, asthma, or sys-
temic anaphylaxis. T cells constitute a large population
of cellular infiltrate in allergic inflammation, and a dys-
regulated immune response appears to be an important
pathogenetic factor. Cardinal events during allergic in-
flammation can be classified as activation, organ-selective
homing, survival and reactivation, and effector functions
of immune system cells.4 T cells are activated by aeroaller-
gens, food antigens, autoantigens, and bacterial superanti-
gens in allergic inflammation. They are under the influence
of skin, lung, or nose-related chemokine networks, and
J ALLERGY CLIN IMMUNOL
VOLUME 119, NUMBER 4
Abbreviations used
LPR: Late-phase reaction
PIT: Peptide immunotherapy
SIT: Specific immunotherapy
SLIT: Sublingual immunotherapy
TLR: Toll-like receptor
Tr1: Type 1 T-regulatory
Treg: T-regulatory
they show organ-selective homing. A prolonged survival
of the inflammatory cells in the tissues and consequent
reactivation is observed in the subepithelial tissues. Finally,
T cells display effector functions, which result in the
induction of hyper-IgE, eosinophil survival, and mucus
hyperproduction; and interact with bronchial epithelial
cells, smooth muscle cells, and keratinocytes, causing
their activation and apoptosis.4,5 Peripheral T-cell toler-
ance to allergens can overcome all of these pathological
events in allergic inflammation because they all require
T-cell activation.
SEQUENTIAL EVENTS IN ALLERGEN-
SPECIFIC IMMUNOTHERAPY AND THEIR
UNDERLYING MECHANISMS
Very early desensitization effect
The underlying immunological mechanisms of aller-
gen-specific immunotherapy (SIT) are continuously being
elucidated (Table I; Fig 1). Very early effects are related
to mast cell and basophil desensitization. Intermediate
effects are related to changes in allergen-specific T cells,
and late affects are related to B cells and IgE as well as
mast cells, basophils, and eosinophils. Although definite
decrease in IgE antibody levels and IgE-mediated skin
sensitivity normally requires years of SIT, most patients
are protected against bee stings already at an early stage
of venom-SIT. An important observation starting from
the first injection is an early decrease in mast cell and ba-
sophil activity for degranulation and systemic anaphylaxis
(Fig 1). Although it seems similar to rapid desensitization
for hypersensitivity reactions to drugs, the mechanism
of this desensitization effect is yet unknown. Acute oral
desensitization to penicillin V in mice demonstrated that an-
tigen-specific mast cell desensitization is one of the main un-
derlying mechanisms for oral desensitization.6 It has been
shown that mediators of anaphylaxis (histamine and leuko-
trienes) are released during SIT and sting challenges without
inducing a systemic anaphylactic response.7 Their piece-
meal release below the threshold of systemic anaphylaxis
may decrease the granule content of mediators and also
may affect the threshold of activation of mast cells and ba-
sophils, because decreased mediator release in these cells
is a well demonstrated feature in in vitro analysis a short
time after the start of allergen-SIT.7-9 Although there are
fluctuations and a risk for developing systemic anaphylaxis
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TABLE I. Effects of allergen-SIT on clinical and
immunologic parameters
Clinical Long-term cure
parameters Decreased clinical symptoms and drug use
Decreased response to allergen challenge tests
Decreased size and cellular influx in skin LPR
Decreased skin type I hypersensitivity response
Improved quality of life
Mast cells Very early desensitization effect
Reduction of tissue numbers
Decrease in mediator release
Decrease in proinflammatory cytokine production
Basophils Very early desensitization effect
Decrease in mediator release
Decrease in proinflammatory cytokine production
Eosinophils Reduction of tissue numbers
Decrease in mediator release
T cells Decreased allergen-induced proliferation
Induction of Treg cells
Increased secretion of IL-10 and TGF-b
Suppression of TH2 cells and cytokines
Decreased T-cell numbers in LPR
B cells Early increase and late decrease in serum
specific IgE
Increased serum specific IgG4
Increased serum specific IgG1 (relatively low
compared with IgG4)
Increased serum specific IgA
Suppressed IgE-facilitated antigen presentation
Dendritic cells Different subsets can be targeted depending on
the type of the adjuvant
Suppressed IgE-facilitated antigen presentation
Monocytes Increased IL-10 production
during the course of allergen-SIT, the suppression of mast
cells and basophils continues to be affected by changes
in other immune parameters such as the generation of
allergen-specific T-regulatory (Treg) cells and decreased
specific IgE.
Generation of Treg cells and peripheral
T-cell tolerance
The induction of a tolerant state in peripheral T cells
represents an essential step in allergen-SIT (Table I; Fig
1). Peripheral T-cell tolerance is characterized mainly
by generation of allergen-specific Treg cells, suppressed
proliferative and cytokine responses against the major
allergen (Fig 2).10-12 Subsets of Treg cells with distinct
phenotypes and mechanisms of action include the natu-
rally occurring thymic selected CD41CD251 Treg cells
and the inducible type 1 Treg (Tr1) cells.13 In allergen-
SIT, peripheral T-cell tolerance is initiated by autocrine
action of IL-10 and TGF-b, which is increasingly pro-
duced by the antigen-specific T cells.11,14,15 The suppres-
sion by these cells could be partially blocked by the use
of neutralizing antibodies against secreted or membrane-
bound IL-10 and TGF-b.12 However, these cells do ex-
press CD4 and CD25, raising the question whether these
are inducible Tr1 cells, which have upregulated CD25,
or naturally occurring CD41CD251 Treg cells that
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FIG 1. Immunologic changes during the course of allergen-SIT. Although there is significant variation between
donors and protocols, starting from the first injection, an early decrease in mast cell and basophil activity and
degranulation and decreased tendency for systemic anaphylaxis is observed. This is followed by generation
of allergen-specific Treg cells and suppression of allergen-specific TH1 and TH2 cells. An early increase of spe-
cific IgE and late decrease is observed. This is in parallel to an increase of IgG4 in particular and, in some stud-
ies, IgG1 and IgA. A significant decrease in the allergen-specific IgE/IgG4 ratio occurs after several months. A
significant decrease in type I skin test reactivity is also observed relatively late in the course. Decrease in tissue
mast cells and eosinophils and release of their mediators and decrease in LPR is observed after a few months.

produce suppressive cytokines.13 In addition, it has been
shown that CD41CD251 Treg cells from atopic donors
have a reduced capability to suppress the proliferation of
CD41CD252 T cells.16 Therefore, it has been suggested
that upregulation of CD41CD251 Treg cells plays a role
in allergen-SIT. TGF-b plays a dual role in allergic dis-
ease: it suppresses allergen-specific T cells and plays a
role in remodeling of the tissues. It remains to be eluci-
dated in allergic inflammation whether the remodeling
and the suppressive roles of TGF-b show an imbalance
that aggravates the disease instead of controlling the
immune response.17
Studies on the mechanisms by which immune re-
sponses to nonpathogenic environmental antigens lead
to either allergy or nonharmful immunity have demon-
strated that Treg cells are dominant in healthy individ-
uals.18,19 If a detectable immune response is mounted, Tr1
cells specific for common environmental allergens consis-
tently represent the dominant subset in healthy individ-
uals. They use multiple suppressive mechanisms, IL-10
and TGF-b as secreted cytokines, and cytotoxic T-lym-
phocyte antigen 4 and programmed death 1 as surface
molecules. Healthy and allergic individuals exhibit all
3—TH1, TH2, and Tr1 allergen-specific subsets—in dif-
ferent proportions.18 Accordingly, a change in the dominant
subset and the balance between TH2 and Treg cells may
lead to either allergy development or recovery. Another
study on healthy immune response to allergens demon-
strated that CD41CD251 Treg cells have been associated
with the spontaneous remission of cow’s milk allergy.
Children who outgrew their allergy (tolerant children)
had higher frequencies of circulating CD41CD251 T cells
and decreased in vitro proliferative responses to bovine
b-lactoglobulin in PBMCs compared with children who
maintained clinically active allergy.20 Several studies
have been reported in other diseases in the same line.
The in vitro proliferative response to nickel of human
CD41 T cells from healthy, nonallergic individuals was
strongly augmented when CD41CD251 Treg cells were
depleted.21 Furthermore, a human in vivo study on immu-
notherapy of rheumatoid arthritis also showed a marked
increase in the number of FoxP31CD41CD251 Treg cells
in peripheral blood.22 CD251 Treg cells are characterized
by the expression of the transcriptional regulator Foxp3
(FOXP3 in human beings), which appears to be the master
switch gene for Treg cell development and function. The
spontaneous development of allergic airway inflamma-
tion, hyper-IgE, and eosinophilia in addition to various
autoimmune diseases in Foxp3 mutant mice provides
compelling evidence for its importance in allergic inflam-
mation.23 Human beings with immune dysregulation
polyendocrinopathy enteropathy X-linked syndrome are
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VOLUME 119, NUMBER 4

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FIG 2. A, Suppression of TH2 cell-mediated features of allergic inflammation by Treg cells. Treg cells use mul-
tiple suppressor factors to regulate undesired activity of effector TH2 cells. IL-10 and TGF-b suppress IgE pro-
duction and induce IgG4 and IgA, respectively. Both cytokines directly suppress allergic inflammation induced
by effector cells such as mast cells, basophils, and eosinophils. In addition, TH2 cells are suppressed by Treg
cells and can therefore no longer provide cytokines such as IL-3, IL-4, IL-5, IL-9, and IL-13. These cytokines are
required for the differentiation, survival, and activity of mast cells, basophils, eosinophils, and mucus-produc-
ing cells, as well as for the tissue homing of TH2 cells and eosinophils (red line, suppression; black line, stim-
ulation). B, Suppression of TH1 cell-mediated features of allergic inflammation by Treg cells. The TH1 cytokine,
IFN-g, in combination with TNF-a and/or FasL, induces apoptosis of smooth muscle cells, keratinocytes, and
bronchial epithelial cells as essential tissue injury events in atopic dermatitis and asthma (red line, suppres-
sion; black line, stimulation). FasL, Fas-ligand; IP-10, IFN-g–inducible protein 10; mig, monokine induced by
IFN-g; iTac, IFN-g–inducible chemoattractant.
 784 Akdis and Akdis
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similarly affected and mostly develop hyper-IgE and
eczema because of mutations in the FOXP3 gene.23 Sup-
porting these findings, a dysregulation of disease-causing
effector T cells is observed in atopic dermatitis lesions in
association with an impaired CD41CD251FoxP31 T-cell
infiltration in the dermis.24
The role of Treg cells is not limited to suppression of
TH2 cells. Peripheral tolerance uses multiple mechanisms
to suppress allergic inflammation. Apparently, Treg cells
contribute to the control of allergen-specific immune re-
sponses in 5 major ways: suppression of antigen-present-
ing cells that support the generation of effector TH2 and
TH1 cells; suppression of TH2 and TH1 cells; suppression
of allergen-specific IgE and induction of IgG4 and/or
IgA; suppression of mast cells, basophils, and eosinophils;
and interaction with resident tissue cells and remodeling.13
Modulation of allergen-specific IgE and IgG
subtype responses during allergen-SIT
Specific IgE in serum and on the surface of mast cells
and basophils bound to FceRI in patients with allergy is
a hallmark of atopic disease. Although peripheral T-cell
tolerance is rapidly induced during SIT, there is no
evidence for B-cell tolerance in the early course.10 Natural
exposure to a relevant allergen is often associated with an
increase in the IgE synthesis. Similarly, SIT frequently in-
duces a transient increase in serum specific IgE, followed
by a gradual decrease over a period of months or years of
treatment (Fig 1).25,26 In pollen-sensitive patients, desen-
sitization prevents elevation of the serum specific IgE
during the pollen season.27 However, the changes in IgE
levels cannot explain the diminished responsiveness to
specific allergen as a result of SIT, because the decrease
in serum IgE is relatively late and does not correlate
with clinical improvement after SIT.
Antibody responses induced during allergen-SIT are
functionally heterogeneous, which may account for the
conflicting data in relation to the protective effects of
IgG.12,25,26 Subclasses of IgG antibodies, especially IgG4,
are thought to capture the allergen before reaching the
effector cell-bound IgE, and thus to prevent the activation
of mast cells and basophils. However, the relationship
between the efficacy of SIT and the induction of aller-
gen-specific IgG subgroups remains a controversial issue,
with serum concentrations of allergen-specific IgG corre-
lating with clinical improvement in some studies but not in
others.28,29 Allergen-specific IgG may be directed against
the same epitopes as IgE, resulting in direct competition
for allergen binding and a blocking effect. By contrast,
induction of IgG specific for other epitopes may result in
a failure of the IgG response to compete with IgE, even
when IgG is present in molar excess. The concept of
blocking antibodies has recently been revaluated. Analysis
of the IgG subtypes induced by SIT has shown specific
increases in IgG1 and particularly IgG4, with levels in-
creasing 10-fold to 100-fold.30,31 There is accumulating
evidence that SIT also influences the blocking activity
on IgE-mediated responses by IgG4, and cellular as-
says are commonly used to investigate these changes.
J ALLERGY CLIN IMMUNOL
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Recently, a novel assay that detects allergen-IgE binding
by using flow cytometry has been used to detect functional
SIT-induced changes in IgG antibody activity. Results
suggest that successful SIT is associated with an increase
in IgG blocking activity that is not solely dependent on the
quantity of IgG antibodies.32,33 It seems to be relevant to
measure the blocking activity of allergen-specific IgG or
IgG subsets, particularly IgG4 and also IgG1, instead of
the crude levels in sera. In this context, the role of anti-
IgE treatment in the induction phase of allergen-SIT on
safety and efficacy has been questioned. Anti-IgE mAb
pretreatment enhances the safety of SIT for allergic rhinitis
and may be an effective strategy to permit more rapid and
higher doses of allergen immunotherapy.34 Its function on
long-term efficacy is still under investigation.
The noninflammatory role for IgG4 may arise because
the IgG4 hinge region has unique structural features that
result in a lower affinity for certain Fcg receptors and
the ability to separate and repair, leading to bispecific an-
tibodies that are functionally monomeric.35 Furthermore,
IgG4 does not fix complement and is capable of inhibiting
immune-complex formation by other isotypes, giving this
isotype anti-inflammatory characteristics. By using well
defined recombinant allergen mixtures, all treated subjects
developed very strong allergen-specific IgG4 and also in-
creased IgG1 antibody responses. Some patients who were
not initially sensitized to Phl p 5 developed strong specific
IgG4, but not IgE antibody responses to that allergen.30
This demonstrates that extract-based antibody measure-
ments may provide incorrect information, and studies on
mechanisms of allergen-SIT should be performed with
single allergens. Nevertheless, IgG4 antibodies can be
viewed as a marker of introduced allergen dose, and
they have the ability to modulate the immune response
to allergen and thus the potential to influence the clinical
response to allergen. In addition, the affinity of newly
produced IgG4 and decreasing IgE to allergens has not
been intensely studied and may have a very decisive
role. Affinity maturation of specific antibodies in allergen
immunotherapy and preseasonal versus postseasonal changes
in their affinity remain to be elucidated.36
IL-10 that is induced and increasingly secreted by SIT
appears to counterregulate antigen-specific IgE and IgG4
antibody synthesis.11 IL-10 is a potent suppressor of
both total and allergen-specific IgE, and it simultaneously
increases IgG4 production. Thus, IL-10 not only generates
tolerance in T cells but also regulates specific isotype
formation and skews the specific response from an IgE-
dominated to an IgG4-dominated phenotype (Fig 2).
The healthy immune response to Der p 1 demonstrated in-
creased specific IgA and IgG4, small amounts of IgG1, and
almost undetectable IgE antibodies in serum.12 House dust
mite–SIT did not significantly change specific IgE levels
after 70 days of treatment; however, a significant increase
in specific IgA, IgG1, and IgG4 was observed.12 The in-
crease of specific IgA and IgG4 in serum coincides with in-
creased TGF-b and IL-10, respectively. This may account
for the role of IgA and TGF-b as well as IgG4 and IL-10
in peripheral mucosal immune responses to allergens in
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healthy individuals.11,37 Most probably the decrease in
IgE/IgG4 ratio during allergen-SIT is a feature of skew
from allergen-specific TH2 to Treg cell predominance.
However, although Treg cell generation happens within
days, a significant decrease in IgE/IgG4 ratio occurs after
years. The reason for the long period between the change
in T-cell subsets but not IgE/IgG4 levels is not easily
explainable by the half-life of antibodies. In this context,
the role of bone marrow-residing IgE-producing plasma
cells with very long life spans remains to be investigated.38
Suppression of effector cells and
inflammatory responses during allergen-SIT
Peripheral T-cell tolerance to allergens, which is char-
acterized by functional inactivation of the cell to antigen
encounter, can overcome both acute and chronic events in
allergic reactions (Fig 2). Allergen-SIT efficiently modu-
lates the thresholds for mast cell and basophil activation
and decreases IgE-mediated histamine release.39 In addi-
tion, IL-10 was shown to reduce proinflammatory cytokine
release from mast cells.40 Furthermore, IL-10 downregu-
lates eosinophil function and activity and suppresses
IL-5 production by human resting TH0 and TH2 cells.41
Moreover, although demonstrated in a model of myocardi-
tis, IL-10 gene transfer significantly reduces mast cell den-
sity, local histamine concentration, and mast cell growth,
and prevents mast cell degranulation.42
Long-term SIT is associated with reduction of not only
the immediate response to allergen provocation but also
the late-phase reaction (LPR) in the nasal and bronchial
mucosa or in the skin. The mechanism of LPR is different
from the mast cell–mediated immediate reaction and
involves the recruitment, activation, and persistence of
eosinophils and activated T cells at the sites of allergen
exposure.3 Successful SIT results not only in the increase
of allergen concentration necessary to induce immediate
or LPR in the target tissue but also in the decreased re-
sponses to nonspecific stimulation. Bronchial, nasal, and
conjunctival hyperreactivity to nonspecific stimuli, which
seems to reflect underlying mucosal inflammation, de-
creases after SIT and correlates with clinical improvement.43
During birch pollen SIT, reduced plasma levels of eosino-
phil cationic protein, a marker of eosinophil activation, as
well as chemotactic factors for eosinophils and neutrophils
correlated with decreased bronchial hyperreactivity and
clinical improvement.44 Inhibition by SIT of the seasonal
increase in eosinophil priming has also been demon-
strated.45 In biopsies taken during grass pollen SIT, de-
creased eosinophil and mast cell infiltration in nasal and
bronchial mucosa after SIT correlated with the anti-inflam-
matory effect.46
MECHANISMS OF SUBLINGUAL
IMMUNOTHERAPY
Because of potentially severe, albeit infrequent, side
effects associated with injection SIT, mucosal routes of
administration are being investigated to conduct allergenic
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desensitization.47 Although its safety and efficacy have
now been largely documented, much remains to be in-
vestigated on the immunologic mechanisms underlying
sublingual immunotherapy (SLIT). A meta-analysis of
the double-blind, placebo-controlled trials performed in
the past decade has shown that SLIT is clinically effica-
cious although, at present, the treatment benefit is approx-
imately half that achieved with subcutaneous SIT.48 The
immunologic mechanisms of sublingual SIT seem to be
similar to subcutaneous SIT, although the magnitude of
the change in most parameters is modest or no change
has been observed. It seems likely that the contact of the
allergen with the oral mucosa is critical for the success of
SLIT.49 It is postulated that most likely oral Langerhans
cells are critically involved in this process.50 During
SLIT, the allergen is captured within the oral mucosa by
oral Langerhans cells, and subsequently these cells mature
and migrate to proximal draining lymph nodes. Those
local lymph nodes may favor the production of blocking
IgG antibodies and the induction of T lymphocytes with
suppressive function.51,52 Most studies using SLIT have
reported increased levels of serum IgG4 with a relative-
ly modest increase compared with injection immunother-
apy.53 There is no consistency in T-cell and IgE and
effector cell responses, and a significant number of studies
has failed to detect systemic immunologic changes.48,53
This may be related to the different doses of allergen ad-
ministered in different studies, or to the development of
more localized immunologic changes. In a recent study,
PBMCs were stimulated with pollen allergen extract after
1 and 2 years of SLIT. The expression of IL-10 mRNA
was increased in both high and low doses and showed a
positive correlation with TGF-b expression. IL-5 was sup-
pressed with a high dose, which negatively correlated with
TGF-b.54 In a recently reported birch pollen extract SLIT,
patients showed improved nasal provocation scores to
birch pollen; however, apple-induced oral allergy syn-
drome caused by cross-reactivity was not significantly re-
duced. Bet v 1–specific T-cell tolerance to all epitopes and
those cross-reactive with Mal d 1 from apple were shown.
However, neither Mal d 1–specific IgE and IgG4 levels nor
Mal d 1–induced T-cell proliferation changed signifi-
cantly, probably because of noncross-reactive epitopes.55
These results may explain why pollen-associated food al-
lergy is frequently not ameliorated by pollen immunother-
apy. Although SLIT is increasingly being used, several
points need further investigation, such as its efficacy in
asthma, its mechanisms of action, the optimal dose and
time to be administered, its combination with injection im-
munotherapy, age of onset for its safe use in young chil-
dren, and its preventive role in the development of allergy.
UNDERLYING MECHANISMS OF NOVEL
AND EMERGING SIT VACCINES
Intensive studies are being performed to improve effi-
cacy and safety of allergen-SIT (Table II). A basic require-
ment for an allergen vaccine in achieving successful SIT
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TABLE II. Novel approaches for future of allergen-SIT
Type of the vaccine/approach
59
Fusion of major allergens
Chimeric allergens60
Fragments61
Peptides of major allergens58
Polymers of major allergens61
Unrefolded native allergens57
Mixture of several major recombinant allergens30
GpG oligonucleotide-conjugated allergens64
Allergens coupled to viruslike particles65
Combination of conventional SIT with anti-IgE34
Intralymphatic vaccination62
without risk of anaphylaxis is to express T-cell epitopes,
which induce T-cell tolerance and lack antibody-binding
sites that mediate IgE cross-linking.56 Conformation de-
pendence of B-cell epitopes and linearity of T-cell epitopes
may induce a different regulation of allergen-specific
T-cell cytokine toward a nonallergic phenotype. Native
allergens use IgE-facilitated antigen presentation by den-
dritic cells and B cells, which activates T cells to produce
TH2-type cytokines and B cells to produce further IgE in a
secondary response. In contrast, B-cell epitope deleted al-
lergens, which do not bind IgE, do not initiate effector cell
degranulation. They use phagocytotic or pinocytic antigen
uptake mechanisms in dendritic cells, macrophages, and B
cells.57 T cells may be subsequently induced to generate a
balanced TH0/TH1-type cytokine pattern in lower quanti-
ties as well as T-cell tolerance, which involves Treg cells.
Accordingly, targeting T cells and bypassing IgE by modi-
fied allergens will enable the administration of higher
doses of allergens, which is required to induce T-cell
tolerance without the risk of anaphylaxis.57
In line with this concept, immunotherapy using pep-
tides (PIT) is an attractive approach for safe SIT. To
date, clinical trials of PIT have been performed in 2 aller-
gies.58 Induction of T-cell tolerance and increased IL-10
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Description and mechanism
Several major allergens (Api m 1, Api m 2) are fused and expressed as a
single recombinant protein. IgE binding is attenuated. T-cell reactivity is
preserved. Preventive effect on generation of IgE is demonstrated in mice.
Fragments of major allergens (Api m 1, Api m 2, Api m 3) are fused
and expressed as a single protein. IgE binding is attenuated. T-cell
reactivity is preserved. Preventive effect on generation of IgE is
demonstrated in mice.
Major allergen (Bet v 1) is divided into non-IgE binding fragments. IgE
binding is attenuated. T-cell reactivity is preserved. A multicenter
clinical trial has been reported.
Non-IgE binding T-cell epitope peptides (Fel d 1, Api m 1) have been
used in cat and bee venom allergy.
Major allergen (Bet v 1) is trimerized. Mast cell, basophil degranulation
is attenuated. T-cell reactivity is preserved. A multi-center clinical trial
has been reported.
Major recombinant allergens (Api m 1, Bet v 1) are not refolded to the
native conformation. This decreases or abolishes IgE binding but
preserves T-cell reactivity.
Clinical efficacy of a mixture of 5 recombinant grass pollen allergens
(Phl p 1, Phl p 2, Phl p 5a, Phl p 5b, Phl p 6) in reducing symptoms
and need for symptomatic medication in patients with grass pollen
allergy was demonstrated.
Major allergen (Amb a 1) is bound to a TLR9-triggering CpG
oligonucleotide. In this way, allergen and innate immune response
stimulating agent are expressed in 1 molecule.
Der p 1 peptides coupled to highly repetitive virus capsid-like
recombinant particles induced high specific IgG titers.
Anti-IgE mAb pretreatment enhances the safety of SIT for allergic
rhinitis. Its role on long-term efficacy is still under investigation.
Allergen-SIT vaccines administered directly into a lymph node are
currently being investigated. The aim is to deliver high amounts of
allergens into secondary lymphatic organs.
production have been demonstrated both in cat Fel d
1 and bee venom Api m 1 PITs.58 A potential barrier to
PIT of allergy is the apparent complexity of the aller-
gen-specific T-cell response in terms of epitope use and
dominant epitopes in human beings and stability of pep-
tides. To overcome these problems, genetically engi-
neered recombinant hybrid molecules that span the
whole T-cell repertoire but do not bind IgE have been
developed. In cysteine-containing proteins, folding is
complicated by the formation of intramolecular and inter-
molecular disulphide bond formation, whereas any
formed disulphide bond can fix the conformation and
limits the freedom of further folding processes. With an
increasing number of cysteines, the probability of a cor-
rect or nativelike folding rapidly decreases because of
the increasing probability of incorrect disulfide-bound
formation. A fusion protein consisting of the 2 major al-
lergens of bee venom, Api m 1 and Api m 2, has been
generated to investigate this concept. Destroyed confor-
mational B-cell epitopes but intact T-cell epitopes of the
2 allergens characterize this protein. By providing
decreased allergenicity with preserved T-cell tolerance–
inducing capacity, the Api m [1/2] fusion protein repre-
sents a novel vaccine prototype for allergen-SIT.59
J ALLERGY CLIN IMMUNOL
VOLUME 119, NUMBER 4
Another interesting approach was to cut the major aller-
gens to fragments and fuse them in a different order with-
out missing any T-cell epitopes in 1 reassembled mosaic
allergen.60 In this study, 2 fragments of Api m 1, 3 frag-
ments of Api m 2, and Api m 3 are reassembled in a
different order with overlapping residues, so no T-cell
epitopes are missed. Single injection of both vaccines,
which only target T cells, demonstrated a preventive ef-
fect on IgE generation in mice. The advantage of these
2 approaches is that only 1 molecule has to be produced
and purified instead of several recombinant allergens.
T-cell epitopes are preserved, and B-cell epitopes can be
deleted or preserved depending on the type of the fusion
molecule. Another interesting approach was to use frag-
ments and a trimer of major birch pollen allergen Bet v
1 to treat birch pollen allergy. A double-blind, placebo-
controlled study has been completed in 3 centers, which
demonstrated an increase in IgG1, IgG2, IgG4, and IgA
and suppression of seasonal increases of IgE.61 In a differ-
ent approach, the effectiveness of a mixture of 5 recombi-
nant grass pollen allergens in reducing symptoms and a
need for symptomatic medication in patients with grass
pollen allergy were demonstrated. All treated subjects de-
veloped strong allergen-specific IgG1 and IgG4 antibody
responses.30 Allergen-SIT vaccines are generally admin-
istered subcutaneously, intradermally, or sublingually,
from where they must reach secondary lymphatic organs
to induce an immune response. In a mouse study, an
MHC class I–binding peptide from lymphocytic chorio-
meningitis virus enhanced immunogenicity by as much
as 106 times compared with subcutaneous and intradermal
vaccination. Intralymphatic administration induced CD8
T-cell responses with strong cytotoxic activity and IFN-g
production that conferred long-term protection against vi-
ral infections and tumors.62 The efficacy of allergen-SIT
vaccines administered directly into inguinal lymph nodes
of human beings is currently being investigated.
Allergen-SIT uses aluminium hydroxide as an adju-
vant. These preparations have generally proven to be
efficacious and have a good safety profile, but might be
improved in efficacy. A new class of adjuvants—so-called
immune response modifiers— act on antigen-presenting
cells through the Toll-like receptors (TLRs), which recog-
nize pathogen-associated molecular patterns on microor-
ganisms. Depending on the type of TLR, different types
of antigen-presenting cells can be targeted. TLR-trigger-
ing compounds that can control the overexpression of
TH2 cytokines or skew the TH1:TH2 balance toward
a TH1 profile have been effective in murine models of
allergy.56 Oligodeoxynucleotides containing immuno-
stimulatory CpG motifs that trigger TLR9, linked to the
allergen in ragweed allergy in human beings, have been
used. Amb a 1–immunostimulatory DNA sequence con-
jugate SIT led to a prolonged shift from TH2 immunity
toward TH1 immunity and appeared to be safe.63 In a re-
cent study, the same Amb a 1 CpG conjugate was shown
to be effective for the treatment of allergic rhinitis in 2 con-
secutive seasons. Although an early increase in Amb a 1–
specific IgE was observed during the injection phase, a
Akdis and Akdis 787
feature articles
Reviews and
seasonal increase in Amb a 1–specific IgE did not occur,
and a reduction in the number of IL-4–positive basophils
was reported.64 In another study, vaccination with a pep-
tide antigen covalently coupled to highly repetitive virus-
like particles induced high IgG antibody titers in human
beings, suggesting the possibility of using allergens cou-
pled to viruslike particles in allergen-SIT.65 As a different
immunologic approach, the fusion of allergens with hu-
man Fcg has been reported to inhibit allergen-induced
basophil and mast cell degranulation by cross-linking
Fcg and FceRI receptors.66
CONCLUSION
There is increasing evidence to support IL-10 and/or
TGF-b secreting Treg cells and immunosuppressive cy-
tokines as key players in mediating successful allergen-
SIT and a healthy immune response to allergens. In
addition to allergy, these mechanisms may have implica-
tions in autoimmunity, graft-versus-host disease, tumor
cell growth, parasite survival, chronic infections, and the
development of AIDS. In sensitized individuals, periph-
eral T-cell tolerance represents the key mechanism in
healthy immune responses to allergens. Peripheral toler-
ance to allergens induced by allergen-SIT involves control
of the allergen-specific immune response in multiple
phases including specific T-cell suppression, generation of
noninflammatory antibody isotypes such as IgG4 and IgA,
suppression of IgE and type 1 hypersensitivity responses,
and suppression of LPRs and mast cells, eosinophils, and
basophils. Taking the recent advances in knowledge of
peripheral tolerance mechanisms into account, develop-
ments of safer approaches and more efficient methods of
allergen-SIT await.
New approaches to allergen-SIT, such as the use of
recombinant proteins, peptides, fragments, and hybrid
allergens, are promising, but are only in an early stage of
human clinical trials. There are several essential require-
ments underlying novel strategies for the development
of safe and more efficient allergen-SIT vaccines: (1) the
vaccine should be constituted of perfectly well standard-
ized native proteins or recombinant allergens; (2) the
vaccine should induce tolerance in allergen-specific ef-
fector T cells, suppress IgE production, and promote IgG4
or IgA isotype blocking antibody production; (3) the vac-
cine should not induce severe side effects and should be
well tolerated; (4) the vaccine should be easily adminis-
tered; (5) the treatment should achieve clinical success
and long-term protection in a short time with few doses;
and (6) early biological/immunologic markers to assess
clinical success, before the onset or early in the course
of the treatment, should be identified.
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